tbuckley/cabot-search huggingface dataset:
Improved gut microbiome recovery following drug therapy is linked to abundance and replication of probiotic strains
Authors: Jamie FitzGerald, Shriram Patel, Julia Eckenberger, Eric Guillemard, Patrick Veiga, Florent Schäfer, Jens Walter, Marcus J Claesson, Muriel Derrien
Journal: Gut Microbes (2022)

Probiotics have been used for decades to alleviate the negative side-effects of oral antibiotics, but our mechanistic understanding on how they work is so far incomplete. Here, we performed a metagenomic analysis of the fecal microbiota in participants who underwent a 14-d Helicobacter pylori eradication therapy with or without consumption of a multi-strain probiotic intervention (L. paracasei CNCM I-1518, L. paracasei CNCM I-3689, L. rhamnosus CNCM I-3690, and four yogurt strains) in a randomized, double-blinded, controlled clinical trial. Using a strain-level analysis for detection and metagenomic determination of replication rate, ingested strains were detected and replicated transiently in fecal samples and in the gut during and following antibiotic administration. Consumption of the fermented milk product led to a significant, although modest, improvement in the recovery of microbiota composition. Stratification of participants into two groups based on the degree to which their microbiome recovered showed i) a higher fecal abundance of the probiotic L. paracasei and L. rhamnosus strains and ii) an elevated replication rate of one strain (L. paracasei CNCMI-1518) in the recovery group. Collectively, our findings show a small but measurable benefit of a fermented milk product on microbiome recovery after antibiotics, which was linked to the detection and replication of specific probiotic strains. Such functional insight can form the basis for the development of probiotic-based intervention aimed to protect gut microbiome from drug treatments.
Trajectories in <scp>New York</scp> Heart Association functional class in heart failure across the ejection fraction spectrum: data from the <scp>Swedish</scp> Heart Failure Registry
Authors: Felix Lindberg, Lars H. Lund, Lina Benson, Ulf Dahlström, Patric Karlström, Cecilia Linde, Giuseppe Rosano, Gianluigi Savarese
Journal: European Journal of Heart Failure (2022)

To investigate incidence, predictors and prognostic implications of longitudinal New York Heart Association (NYHA) class changes (i.e. improving or worsening vs. stable NYHA class) in heart failure (HF) across the ejection fraction (EF) spectrum.From the Swedish HF Registry, 13 535 patients with EF and ≥2 NYHA class assessments were considered. Multivariable multinomial regressions were fitted to identify the independent predictors of NYHA change. Over a 1-year follow-up, 69% of patients had stable, 17% improved, and 14% worsened NYHA class. Follow-up in specialty care predicted improving NYHA class, whereas an in-hospital patient registration, lower EF, renal disease, lower mean arterial pressure, older age, and longer HF duration predicted worsening. The association between NYHA change and subsequent outcomes was assessed with multivariable Cox models. When adjusting for the NYHA class at baseline, improving NYHA class was independently associated with lower while worsening with higher risk of all-cause and cardiovascular mortality, and first HF hospitalization. After adjustment for the NYHA class at follow-up, NYHA class change did not predict morbidity/mortality. NYHA class assessment at baseline and follow-up predicted morbidity/mortality on top of the changes. Results were consistent across the EF spectrum.In a large real-world HF population, NYHA class trajectories predicted morbidity/mortality after extensive adjustments. However, the prognostic role was entirely explained by the resulting NYHA class, i.e. the follow-up value. Our results highlight that considering one-time NYHA class assessment, rather than trajectories, might be the preferable approach in clinical practice and for clinical trial design.
Mediators of Racial Disparities in Heart Dose Among Whole Breast Radiotherapy Patients
Authors: Christina Hunter Chapman, Reshma Jagsi, Kent A Griffith, Jean M Moran, Frank Vicini, Eleanor Walker, Michael Dominello, Eyad Abu-Isa, James Hayman, Anna M Laucis, Melissa Mietzel, Lori Pierce
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Racial disparities in survival of patients with cancer motivate research to quantify treatment disparities and evaluate multilevel determinants. Previous research has not evaluated cardiac radiation dose in large cohorts of breast cancer patients by race nor examined potential causes or implications of dose disparities. Methods We used a statewide consortium database to consecutively sample 8750 women who received whole breast radiotherapy between 2012 and 2018. We generated laterality- and fractionation-specific models of mean heart dose. We generated patient- and facility-level models to estimate race-specific cardiac doses. We incorporated our data into models to estimate disparities in ischemic cardiac event development and death. All statistical tests were 2-sided. Results Black and Asian race independently predicted higher mean heart dose for most laterality-fractionation groups, with disparities of up to 0.42 Gy for Black women and 0.32 Gy for Asian women (left-sided disease and conventional fractionation: 2.13 Gy for Black women vs 1.71 Gy for White women, P &amp;lt; .001, 2-sided; left-sided disease and accelerated fractionation: 1.59 Gy for Asian women vs 1.27 Gy for White women, P = .002). Patient clustering within facilities explained 22%-30% of the variability in heart dose. The cardiac dose disparities translated to estimated excesses of up to 2.6 cardiac events and 1.3 deaths per 1000 Black women and 0.7 cardiac events and 0.3 deaths per 1000 Asian women vs White women. Conclusions Depending on laterality and fractionation, Asian women and Black women experience higher cardiac doses than White women. This may translate into excess radiation-associated ischemic cardiac events and deaths. Solutions include addressing inequities in baseline cardiac risk factors and facility-level availability and use of radiation technologies.
Why is there a lack of evidence regarding errors and complications in periodontal and implant therapy?
Authors: Leandro Chambrone, Giovanni Zucchelli
Journal: Periodontology 2000 (2022)

Abstract The occurrence of errors, complications, and adverse effects may occur as a consequence of single or multiple events related to the clinician and/or patient. Apparently, the amount of dental literature on these undesirable outcomes has not been as prolific as that obtained for conventional primary periodontal outcome measures. This review explores the potential reasons for the lack of studies reporting on errors and complications in periodontal and implant therapy, as well as other noteworthy methodological aspects, to enlighten their impact on the selection of the best (or most appropriate) “gold standard” periodontal/implant‐related treatment options, and on the overall decision‐making process. The following points were addressed: (a) the importance of reporting errors and complications in clinical research; (b) the adequate reporting of errors and complications in periodontology and dental implantology; and (c) efficacy trials vs effectiveness studies and their impact on the assessment and report of periodontal and implant treatment‐related risks and complications.
Early Molecular Events Mediating Loss of Aquaporin-2 during Ureteral Obstruction in Rats
Authors: Chih-Chien Sung, Brian G. Poll, Shih-Hua Lin, Adrian R. Murillo-de-Ozores, Chung-Lin Chou, Lihe Chen, Chin-Rang Yang, Min-Hsiu Chen, Yu-Juei Hsu, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2022)

Ureteral obstruction is marked by disappearance of the vasopressin-dependent water channel aquaporin-2 (AQP2) in the renal collecting duct and polyuria upon reversal. Most studies of unilateral ureteral obstruction (UUO) models have examined late time points, obscuring the early signals that trigger loss of AQP2.We performed RNA-Seq on microdissected rat cortical collecting ducts (CCDs) to identify early signaling pathways after establishment of UUO.Vasopressin V2 receptor (AVPR2) mRNA was decreased 3 hours after UUO, identifying one cause of AQP2 loss. Collecting duct principal cell differentiation markers were lost, including many not regulated by vasopressin. Immediate early genes in CCDs were widely induced 3 hours after UUO, including Myc, Atf3, and Fos (confirmed at the protein level). Simultaneously, expression of NF-κB signaling response genes known to repress Aqp2 increased. RNA-Seq for CCDs at an even earlier time point (30 minutes) showed widespread mRNA loss, indicating a "stunned" profile. Immunocytochemical labeling of markers of mRNA-degrading P-bodies DDX6 and 4E-T indicated an increase in P-body formation within 30 minutes.Immediately after establishment of UUO, collecting ducts manifest a stunned state with broad disappearance of mRNAs. Within 3 hours, there is upregulation of immediate early and inflammatory genes and disappearance of the V2 vasopressin receptor, resulting in loss of AQP2 (confirmed by lipopolysaccharide administration). The inflammatory response seen rapidly after UUO establishment may be relevant to both UUO-induced polyuria and long-term development of fibrosis in UUO kidneys.
The role of foreign body response in <scp>peri‐implantitis</scp>: What is the evidence?
Authors: Sašo Ivanovski, Peter Mark Bartold, Yu‐Sheng Huang
Journal: Periodontology 2000 (2022)

Abstract Historically, there has been broad consensus that osseointegration represents a homeostasis between a titanium dental implant and the surrounding bone, and that the crestal bone loss characteristic of peri‐implantitis is a plaque‐induced inflammatory process. However, this notion has been challenged over the past decade by proponents of a theory that considers osseointegration an inflammatory process characterized by a foreign body reaction and peri‐implant bone loss as an exacerbation of this inflammatory response. A key difference in these two schools of thought is the perception of the relative importance of dental plaque in the pathogenesis of crestal bone loss around implants, with obvious implications for treatment. This review investigates the evidence for a persistent foreign body reaction at osseointegrated dental implants and its possible role in crestal bone loss characteristic of peri‐implantitis. Further, the role of implant‐related material release within the surrounding tissue, particularly titanium particles and corrosion by‐products, in the establishment and progression in peri‐implantitis is explored. While it is acknowledged that these issues require further investigation, the available evidence suggests that osseointegration is a state of homeostasis between the titanium implant and surrounding tissues, with little evidence that a persistent foreign body reaction is responsible for peri‐implant bone loss after osseointegration is established. Further, there is a lack of evidence for a unidirectional causative role of corrosion by‐products and titanium particles as possible non–plaque related factors in the etiology of peri‐implantitis.
See None, Do None, Teach None: How Dismantling <i>Roe</i> Impacts Medical Education and Physician Training
Authors: Melissa Montoya, Beverly A. Gray
Journal: The American Journal of Bioethics (2022)

This article refers to:Beyond Abortion: The Consequences of Overturning RoeThe Ethics of Access: Reframing the Need for Abortion Care as a Health Disparity
Private Conversations, Public Debate
Authors: Siripanth Nippita, Christina Jung, Johana D. Oviedo, Gwendolyn P. Quinn
Journal: The American Journal of Bioethics (2022)

This article refers to:The End of Roe v. WadeBeyond Abortion: The Consequences of Overturning RoeThe Ethics of Access: Reframing the Need for Abortion Care as a Health Disparity
Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities
Authors: Chen Hu, Jing Yang, Ziping Qi, Hong Wu, Beilei Wang, Fengming Zou, Husheng Mei, Jing Liu, Wenchao Wang, Qingsong Liu
Journal: MedComm (2022)

The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.
The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study
Authors: Joshua I. Barzilay, William Tressel, Mary L. Biggs, Phyllis K. Stein, Jorge R. Kizer, Sanyog G. Shitole, Yakubu Bene-Alhasan, Kenneth J. Mukamal
Journal: Diabetes Care (2022)

The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes.
Genetically Engineered Viral Vectors and Organic‐Based Non‐Viral Nanocarriers for Drug Delivery Applications
Authors: Sakineh Hajebi, Satar Yousefiasl, Ilnaz Rahimmanesh, Alireza Dahim, Sepideh Ahmadi, Firoz Babu Kadumudi, Nikta Rahgozar, Sanaz Amani, Arun Kumar, Ehsan Kamrani, Mohammad Rabiee, Assunta Borzacchiello, Xiangdong Wang, Navid Rabiee, Alireza Dolatshahi‐Pirouz, Pooyan Makvandi
Journal: Advanced Healthcare Materials (2022)

Conventional drug delivery systems are challenged by concerns related to systemic toxicity, repetitive doses, drug concentrations fluctuation, and adverse effects. Various drug delivery systems are developed to overcome these limitations. Nanomaterials are employed in a variety of biomedical applications such as therapeutics delivery, cancer therapy, and tissue engineering. Physiochemical nanoparticle assembly techniques involve the application of solvents and potentially harmful chemicals, commonly at high temperatures. Genetically engineered organisms have the potential to be used as promising candidates for greener, efficient, and more adaptable platforms for the synthesis and assembly of nanomaterials. Genetically engineered carriers are precisely designed and constructed in shape and size, enabling precise control over drug attachment sites. The high accuracy of these novel advanced materials, biocompatibility, and stimuli-responsiveness, elucidate their emerging application in controlled drug delivery. The current article represents the research progress in developing various genetically engineered carriers. Organic-based nanoparticles including cellulose, collagen, silk-like polymers, elastin-like protein, silk-elastin-like protein, and inorganic-based nanoparticles are discussed in detail. Afterward, viral-based carriers are classified, and their potential for targeted therapeutics delivery is highlighted. Finally, the challenges and prospects of these delivery systems are concluded.
Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease
Authors: Lin Dang, Xinyi Cao, Tianye Zhang, Yongzhan Sun, Shanshan Tian, Tianyu Gong, Hui Xiong, Peipei Cao, Yuhao Li, Shengqiang Yu, Li Yang, Lirong Zhang, Tong Liu, Kai Zhang, Jing Liang, Yupeng Chen
Journal: Journal of the American Society of Nephrology (2022)

Emerging evidence indicates that epigenetic modulation of gene expression plays a key role in the progression of autosomal dominant polycystic kidney disease (ADPKD). However, the molecular basis for how the altered epigenome modulates transcriptional responses, and thereby disease progression in ADPKD, remains largely unknown.Kidneys from control and ADPKD mice were examined for the expression of CDYL and histone acylations. CDYL expression and its correlation with disease severity were analyzed in a cohort of patients with ADPKD. Cdyl transgenic mice were crossed with Pkd1 knockout mice to explore CDYL's role in ADPKD progression. Integrated cistromic and transcriptomic analyses were performed to identify direct CDYL target genes. High-sensitivity mass spectrometry analyses were undertaken to characterize CDYL-regulated histone lysine crotonylations (Kcr). Biochemical analysis and zebrafish models were used for investigating CDYL phase separation.CDYL was downregulated in ADPKD kidneys, accompanied by an increase of histone Kcr. Genetic overexpression of Cdyl reduced histone Kcr and slowed cyst growth. We identified CDYL-regulated cyst-associated genes, whose downregulation depended on CDYL-mediated suppression of histone Kcr. CDYL assembled nuclear condensates through liquid-liquid phase separation in cultured kidney epithelial cells and in normal kidney tissues. The phase-separating capacity of CDYL was required for efficient suppression of locus-specific histone Kcr, of expression of its target genes, and of cyst growth.These results elucidate a mechanism by which CDYL nuclear condensation links histone Kcr to transcriptional responses and cystogenesis in ADPKD.
The contemporary management of cancers of the sinonasal tract in adults
Authors: Rajat Thawani, Myung Sun Kim, Asad Arastu, Zizhen Feng, Malinda T. West, Nicholas F. Taflin, Kyaw Zin Thein, Ryan Li, Mathew Geltzeiler, Nancy Lee, Clifton David Fuller, Jennifer R. Grandis, Charalampos S. Floudas, Michael C. Heinrich, Ehab Hanna, Ravi A. Chandra
Journal: CA A Cancer Journal for Clinicians (2022)

Abstract Sinonasal malignancies make up &lt;5% of all head and neck neoplasms, with an incidence of 0.5–1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract—primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T‐cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.
Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice
Authors: Garazi Pena Alzua, Anne Finne Pihl, Anna Offersgaard, Carlos Rene Duarte Hernandez, Zhe Duan, Shan Feng, Ulrik Fahnøe, Christina Sølund, Nina Weis, Mansun Law, Jannick C Prentoe, Jan Pravsgaard Christensen, Jens Bukh, Judith Margarete Gottwein
Journal: Gut (2022)

Objective A prophylactic vaccine is needed to control the HCV epidemic, with genotypes 1–3 causing &gt;80% of worldwide infections. Vaccine development is hampered by HCV heterogeneity, viral escape including protection of conserved neutralising epitopes and suboptimal efficacy of HCV cell culture systems. We developed cell culture-based inactivated genotype 1–3 HCV vaccine candidates to present natively folded envelope proteins to elicit neutralising antibodies. Design High-yield genotype 1a, 2a and 3a HCV were developed by serial passage of TNcc, J6cc and DBN3acc in Huh7.5 cells and engineering of acquired mutations detected by next-generation sequencing. Neutralising epitope exposure was determined in cell-based neutralisation assays using human monoclonal antibodies AR3A and AR4A, and polyclonal antibody C211. BALB/c mice were immunised with processed and inactivated genotype 1a, 2a or 3a viruses using AddaVax, a homologue of the licenced adjuvant MF-59. Purified mouse and patient serum IgG were assayed for neutralisation capacity; mouse IgG and immune-sera were assayed for E1/E2 binding. Results Compared with the original viruses, high-yield viruses had up to ~1000 fold increased infectivity titres (peak titres: 6–7 log10 focus-forming units (FFU)/mL) and up to ~2470 fold increased exposure of conserved neutralising epitopes. Vaccine-induced IgG broadly neutralised genotype 1–6 HCV (EC50: 30–193 µg/mL; mean 71 µg/mL), compared favourably with IgG from chronically infected patients, and bound genotype 1–3 E1/E2; immune-sera endpoint titres reached up to 32 000. Conclusion High-yield genotype 1–3 HCV could be developed as basis for inactivated vaccine candidates inducing broadly neutralising antibodies in mice supporting further preclinical development.
Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed <i>FLT3</i>mut+ AML ineligible for intensive chemotherapy
Authors: Eunice S. Wang, Pau Montesinos, Mark D. Minden, Je-Hwan Lee, Michael Heuser, Tomoki Naoe, Wen-Chien Chou, Kamel Laribi, Jordi Esteve, Jessica K. Altman, Violaine Havelange, Anne-Marie Watson, Carlo Gambacorti-Passerini, Elzbieta Patkowska, Shufang Liu, Ruishan Wu, Nisha Philipose, Jason E. Hill, Stanley C. Gill, Elizabeth Shima Rich, Ramon V. Tiu
Journal: Blood (2022)

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.